1. Field of the Invention
This invention relates to bioadhesive controlled release systems useful for targeted delivery of biologically active ingredients, such as anti-septic or antibacterial materials, anti-inflammatory, and other active ingredients that interdict the attachment, propagation, growth and or colonization of bacteria on teeth or sensory markers such as flavors and cooling agents to biological surfaces comprising the oral cavity and mucous membranes of various tissues, as well as the release of these active ingredients or sensory markers over an extended period of time. More specifically, the invention pertains to biodegradable bioadhesive and mucoadhesive nano-particles for oral hygiene products such as toothpaste or mouthwash, that sustain the release of biological active ingredients for treatment and prevention of periodontal disease or the release of sensory markers that provide extended sensation of freshness and malodor coverage over an extended period of time.
2. Description of the Related Art
Decreasing the amount of bacteria in the mouth has long been the target of personnel working in the health care field. The oral care industry and health research communities have searched for many years for a way to interdict the attachment, propagation, growth and or colonization of bacteria on teeth since adherence of bacteria is the start of a pernicious chain of events leading to the formation of home care-resistant plaque, calculus, and ultimately, tooth-loss. As the life expectancy of people in developing countries has increased, dental care plays a larger role in overall health, and developing countries are becoming more aware of the importance of oral hygiene. Considering the prevalence of periodontal disease, there is an ongoing need for improved, more effective agents, as well as technology, that inhibit plaque growth to maximize the reduction of oral decay and disease associated with plaque formation.
Periodontal disease, also known as pyorrhea or gum disease, is a major cause of tooth loss in adults. Tooth loss from periodontal disease is a significant problem beginning at about age 35, or even younger. It is estimated that about 4 out of 5 persons already have gingivitis and 4 out of 10 have periodontitis. 75% of the U.S. population suffers from periodontal disease and this epidemic costs billions of dollars a year. The greatest single cause of periodontal disease is poor hygiene, indicated by the appearance of bacterial plaque and tartar (calcified plaque). It is believed that plaque and tartar are more sinister when they occur below the gum line than when they occur at or above the gum line.
Several approaches to fight periodontal disease have been described in patents and in literature. One of the approaches uses liposomes to deliver biologically active ingredients to the oral cavity. Several reports of liposome suspensions containing bioadhesive polymers have been published. The problems with using liposomes and structured vesicles as delivery devices are that these types of systems are unstable and can only be used for encapsulation of certain types of materials. Stability has become the major problem limiting the use of liposomes for controlled delivery, both in terms of shelf life and after administration. Liposomes and vesicles do not remain intact or available in vivo for more than a few hours to a couple of days.
U.S. Pat. No. 5,989,535 discloses a polymeric controlled release composition specifically targeted to the organs that contain mucus membranes at the interface. The invention discloses a polymeric bioadhesive composition that delivers drugs to the target tissue in a sustained manner. The bioadhesive polymer is a water dispersible high molecular weight crosslinked polyacrylic acid copolymer with free carboxylic acid groups further crosslinked with a combination mono, di and polyvalent metal ions, cationic polymers and surfactants. The type of metal ion and the concentration can be adjusted to get the desired adhesive properties along with several physical properties that are important to the formulation of dosage forms.
U.S. Pat. No. 5,993,846 discloses methods for making oil-in-water emulsions having mucoadhesive properties. The emulsion includes a hydrophobic core, a surfactant, and a mucoadhesive polymer which is a polymer or copolymer of acrylic acid or methacrylic acid, a poly (methyl vinyl ether/maleic anhydride) copolymer, pectin, alginic acid, hyaluronic acid, chitosan, gum tragacanth, karaya gum or carboxymethylcellulose surrounding the hydrophobic core. Emulsions of this invention contain a bioadhesive macromolecule or polymer in an amount sufficient to confer bioadhesive properties. The bioadhesive macromolecule enhances the delivery of biologically active agents on or through the target surface. The bioadhesive macromolecule may be selected from acidic nonnaturally occurring polymers, preferably having at least one acidic group per four repeating or monomeric subunit moieties, such as poly(acrylic)- and/or poly(methacrylic) acid (e.g., Carbopol, Carbomer), poly(methylvinyl ether/maleic anhydride) copolymer, and their mixtures and copolymers; acidic synthetically modified natural polymers, such as carboxymethylcellulose (CMC); neutral synthetically modified natural polymers, such as (hydroxypropyl)methylcellulose; basic amine-bearing polymers such as chitosan; acidic polymers obtainable from natural sources, such as alginic acid, hyaluronic acid, pectin, gum tragacanth, and karaya gum; and neutral nonnaturally occurring polymers, such as polyvinylalcohol; or their mixtures. The ionizable polymers may be present as free acids, bases, or salts, usually in a final concentration of 0.01-0.5% (w/vol).
U.S. Pat. No. 5,077,051 discloses bioadhesive microcapsules which permit the sustained release of active agents such as therapeutic or cosmetic agents into, the oral cavity. The bioadhesive microcapsules capable of sustained release comprise of xanthan gum, locust bean gum, a bulking agent and an active agent. The microcapsules are spray-dried or coated with wax and are prepared by a process which comprises spray drying a solution comprising the active agent xanthan gum, locust bean gum and a bulking agent.
U.S. Pat. No. 5,403,578 discloses a stable tooth and gum dentifrice that includes a non-aqueous carrier containing urea, hydrated silica, fluoride, sodium bicarbonate, pyrophosphate, and a peroxide, one or more of the ingredients being microencapsulated and which in use functions as an aid in preventing periodontal disease by reducing incidents of plaque as well as controlling tartar formation, and also as an aid in preventing dental caries and oral odors; and the method of compounding such improved tooth and gum paste. The microencapsulated peroxide may consist of a blend of 75% by weight of calcium peroxide and 25% by weight of calcium hydroxide. The peroxide constituent is provided with an ethylcellulose coating that consists of 6.5% by weight of the finished product.
U.S. Pat. No. 6,007,795 discloses a method for inhibiting bacteria in the mouth of a patient which includes placing a particle containing a degradable material and an anti-microbial agent in the mouth of the patient. In general, the invention features a method for inhibiting bacteria in the mouth of a patient that includes placing a particle containing a degradable material and an anti-microbial agent into the mouth of a patient. The saliva in the mouth causes the degradable material in the particle to degrade, resulting in the release of the anti-microbial agent in a controlled manner over time. The exterior of the particle is water-stable allowing the particles to be incorporated into, for example, aqueous rinses or pastes without the water in the rinse or paste causing the degradable material to degrade prematurely, prior to use.
WO 93/00076 discloses a drug delivery system of microparticles having a spherical core composed of a biopolymer, preferably a protein such as albumin or gelatin, which typically has been crosslinked or denatured to maintain its structural coherency. The spherical core is suggested to be combined with a bioadhesive polymer.
U.S. Pat. No 5,061,106, discloses capsules or microspheres in the tuft holes in which the bristles of a toothbrush are mounted. The capsules or microspheres include a disinfectant or medicant that is released during use. A dye may also be included in the structures. The dye also is released over time to enable the user to become aware of when the contents of the capsules are depleted.
U.S. Pat. No. 5,939,080 discloses oral compositions and methods for reducing plaque in a human or lower animal subject comprising applying to the teeth of the subject an oral composition comprising one or more hydrophobic solvents having one or more characteristics selected from the group consisting of a hydrogen bonding parameter of less than about 7.0 and a water solubility of less than about 10%; one or more non-polymeric surfactants wherein the weight ratio of hydrophobic solvent to non-polymeric surfactant is from about 30:1 to about 1:2; and one or more aqueous carriers; wherein the oral composition is in the form of a toothpaste or mouthrinse, is non-ingestible, and has a pH of from about 5.0 to about 9.5. Preferred hydrophobic solvents include triacetin, diethyl malate, diethyl succinate, benzyl alcohol, phenylethyl alcohol, ethyl acetate, diethyl sebacate, ethyl acetoacetate, diethyl tartrate, butyl lactate, and ethyl lactate. The most preferred hydrophobic solvents are triacetin, diethyl malate, dietihyl succinate, benzyl alcohol, phenylethyl alcohol, and butyl lactate. Suitable non-polymeric surfactants are those which are reasonably stable and foam throughout a wide pH range. The non-polymeric surfactants may be anionic, select nonionic, amphoteric, zwitterionic, cationic, or mixtures thereof.
U.S. Pat. No. 5,976.506 discloses oral care products such as toothpastes with an improved sensorially-perceivable cleaning benefit. This is achieved by the inclusion in the oral care products of agglomerates, substantially free from organic and/or inorganic binding agents, whereby the agglomerates are made of at least two, chemically and/or physically different particulate materials of specified particle sizes. The inclusion of materials having a therapeutic benefit on the teeth or gums in the agglomerates such as zinc citrate provides for a further benefit in that this material is slowly released from the agglomerates, thus providing for a delivery of this material over a longer period. Upon use, the gritty-feeling agglomerates will break-down into smaller particles, thus giving the consumer the feeling of initial cleaning and subsequent polishing.
U.S. Pat. No. 5,955,502 describes the use of fatty acid esters as bioadhesive substances. The fatty acid esters of the invention have molecular weights below about 1000 dalton and the fatty acid component of the fatty acid ester is a saturated or unsaturated fatty acid having a total number of carbon atoms of from C8 to C22. Bioadhesive properties where observed for fatty acid esters of glyceryl monooleate, glyceryl monolinoleate or glyceryl monolinolenate. A method is described for administering active or protective substance to undamaged or damaged skin or mucosa of an animal such as a human by combining the active or protective substance with a bioadhesive fatty acid ester. The created particles have no charge on their surface.
U.S. Pat. No. 4,780,320 discloses a controlled release drug delivery system for placement in the periodontal pocket. The microparticles are prepared by the solvent evaporation process and are between 10 and 500 microns in size. The matrix of the microparticles consist of cellulose acetate, ethylcellulose, polystyrene, polysulfone, polycarbonate and lacticglycolic acid copolymers.
U.S. Pat. No. 6,042,792 disclose controlled, time-release microparticulate active and bioactive compositions, including perfuming compositions, for targeted delivery to skin, hair and fabric. Such compositions include the active or bioactive material in single phase, solid solution in a wax or polymer matrix also having coated thereon or containing a compatible surfactant. Also described are processes and apparatus for preparing such compositions and processes for using the same.
In conventional controlled release systems no precautions are made in order to localize the delivery system after administration and, furthermore, the contact time in vivo between the controlled release system and a particular site is often so short that no advantages are to be expected with respect to, e.g., modifying tissue permeability.
It is desirable to provide a biodegradable bioadhesive/mucoadhesive nano-particle controlled release systems that provide targeted delivery and extended release of biological active ingredients and/or sensory markers for oral and hygiene product, wherein the release rate of the biological active ingredient is synchronized with that of a sensory marker.
The present invention relates to a controlled release delivery system comprising biodegradable bioadhesive nano-particles to provide site-specific delivery of biologically active ingredients or sensory markers for targeting and adhering to biological surfaces comprising the oral cavity and mucous membranes of various tissues. The nano-particle of the present invention sustains the release of the biological active ingredients or sensory markers over an extended period of time. The present invention also provides a method for making biodegradable nano-particles having bioadhesive properties.
The nano-particles of the present invention comprise a cationic surfactant that is entrapped and fixed to the particle surface. The bioadhesive properties of the nano-particles are attributed to the positively charged surfactant entrapped on the particle surface as the hydrophobic ends of the surfactants are embedded in the solid core and the hydrophilic ends are exposed on the surface of the nano-particles. The cationic surface active materials useful in the present invention, are believed to attach to tooth surfaces via a complexing interaction between the cationic portion of the material and the proteinaceous portion of the tooth and thus predispose or condition the surface of the tooth so that the nano-particles will then adhere to the surface.
Preferably, the nano-particles are formed of a solid inner core. The combination of a solid inner core with a cationic exterior provides several advantages of the nano-particles as compared with conventional microspheres, lipospheres, and microparticles, including high dispersibility in an aqueous medium, and a release rate for the entrapped substance that is controlled by the hydrophobic material barrier properties as well as the barrier properties of the hydrophilic layer of cationic surfactant. There are also many advantages over other dispersion-based delivery systems. Nano-particles have increased stability as compared to emulsion-based delivery systems, including vesicles and liposomes, and are more effectively dispersed than most suspension based systems. The substance to be delivered does not have to be soluble in the vehicle since it can be dispersed in the solid matrix. The nano-particles of the present invention also have a lower risk of reaction of substance to be delivered with the vehicle than in emulsion systems because the vehicle is a solid inert material. The altering of either, or both, the inner solid core or the outer surfactant layer can manipulate the release rate of the substance from the nano-particles.
The bioadhesive nano-particle compositions of the present invention can generally be incorporated into any suitable oral hygiene product known in the art. Exemplary oral hygiene products include gels, chewing gums, toothpaste, and mouthwash. The oral hygiene product can be appropriately selected depending upon the physical location that the nano-particles are to be delivered to, as well as the intended use of the nano-particles. The above-described exemplary oral hygiene products are preferred in accordance with the present invention, since they permit effective delivery of the bioadhesive nano-particles into the oral cavity. The toothpaste or mouthwash, containing the biodegradable bioadhesive nano-particles is useful for treatment and prevention of periodontal disease and extended sensation of freshness and malodor coverage in the mouth over an extended period of time. Another aspect of the present invention is to provide oral hygiene products, such as toothpaste or mouthwash, containing the biodegradable bioadhesive nano-particles where the release rate of the biological active ingredients is synchronized with that of a sensory marker to convey to the consumer the product performance.
In another aspect of the present invention the oral hygiene products containing the nano-particles of the invention are useful for targeted delivery of biological active ingredients into the periodontal pocket. The controlled release system of the present invention takes advantage of the anatomical features of the gingiva and adjacent tissues, as a site that can hold the nano-particles for a prolonged period of time. It has also been found that the junctional epithelium, which joins the tooth surface and the keratinised gingival oral epithelium, is a thin, non-keratinised tissue, lacking membrane-coating granules which make this region highly permeable to the nano-particles of the present invention.
Accordingly, the invention provides a biodegradable bioadhesive nano-particle for oral hygiene compositions of matter characterized by one or more of the following:
(i) site-specific delivery of biologically active ingredients or sensory markers, targeting and adhering to biological surfaces comprising the oral cavity and mucous membranes of various tissues;
(ii) controlled, continuous release of effective levels of biological active ingredients or sensory markers over an extended period of time;
(iii) extended sensation of freshness or malodor coverage in the mouth over an extended period of time; and
(iv) the release rate of the biological active ingredients is synchronized with that of a sensory marker.
The invention also provides a method for producing the bioadhesive nano-particles, which comprises the steps of:
heating a hydrophobic core material to a temperature above the material melting point;
dissolving or dispersing the active ingredients or the sensory marker into the melt;
dissolving or dispersing a positively charged surfactant, the biological active agents and the sensory marker in the aqueous phase;
heating the composition to a temperature above the melting point of the formed mixture composed of the hydrophobic materials, active ingredients or the sensory markers;
mixing the hot melt with the aqueous solution to form a suspension;
high shear homogenization of the suspension at a temperature above the melting temperature until a homogeneous fine suspension is obtained; and
rapidly cooling the suspension to below the melting point of the core material mixture composed of the hydrophobic materials, active ingredients, or sensory markers to form a dispersion.
The introduction of active agents such as anti-septic or antibacterial materials, anti-inflammatory, and other such active agents targeting biological surfaces, comprising the oral cavity and mucous membranes of various tissues, into the oral cavity by sustained release has the advantage of reducing the number of times an active agent must be administered, and further provides a uniform distribution of the active agent over an extended period of time. Nano-particles, due to their small size, have been found to penetrate regions that may be inaccessible from other delivery systems, such as the periodontal pocket areas below the gum line. The use of biodegradable nano-particles as intra-pocket delivery systems also has the advantage that there is no need to remove them from the treated area.
Bioadhesive substances, also denoted mucoadhesive substances, are generally known to be materials that are capable of being bound to a biological membrane and retained on that membrane for an extended period of time. Compared with conventional controlled release systems, bioadhesive controlled release systems have the following advantages:
i) a bioadhesive controlled release system localizes a biological active ingredient in a particular region, thereby improving and enhancing the bioavailability for active ingredients which may have poor bioavailability by themselves,
ii) a bioadhesive controlled release system leads to a relatively strong interaction between a bioadhesive substance and a mucosa, such an interaction contributes to an increasing contact time between the controlled release system and the tissue in question and permits localization of the active released from the controlled release system to a specific site,
iii) a bioadhesive controlled release system prolongs delivery of biological active ingredients in almost any non-parenteral route,
iv) a bioadhesive controlled release system can be localized on a specific site with the purpose of local therapy,
v) a bioadhesive controlled release system can be targeted to specific diseased tissues, and
vi) a bioadhesive controlled release system is useful when conventional approaches are unsuitable, such as for certain biological active ingredients which are not adequately absorbed.